Elsevier

The Lancet

Volume 351, Issue 9107, 28 March 1998, Pages 950-953
The Lancet

Early Report
Anti-inflammatory cytokine profile and mortality in febrile patients

https://doi.org/10.1016/S0140-6736(05)60606-XGet rights and content

Summary

Background

An anti-inflammatory cytokine profile on whole-blood stimulation in vitro is associated with fatal outcome of meningococcal disease. We investigated whether an anti-inflammatory cytokine profile in the circulation is associated with adverse outcome in other infectious diseases.

Methods

We enrolled 464 consecutive patients (272 men, 192 women) who presented to hospital with fever (≥38·2°C). On admission we measured plasma interleukin 10 (IL-10) and tumour necrosis factor α (TNα), and collected clinical and microbiological data on the febrile illness, then followed up all patients for clinical outcome.

Findings

In at least 399 of the 464 patients fever was caused by infection. 33 patients died after a median hospital stay of 11 days (interquartile range 3–20). Concentrations of IL-10 were significantly higher in non-survivors (median 169 pg/mL [IQR 83–530]) than in survivors (median 88 pg/mL [42–235], p=0·042). When dichotomised around the median, the mortality risk was two times higher in patients who had high concentrations of IL-10 than in those with low concentrations (relative risk 2·39 [95% Cl 1·07–5·33]), in patients with low and high concentrations of TNFα. In the 406 patients without haemodynamic deterioration in the first 24 h, IL-10 was higher and TNFα lower in patients who died than in those who survived. The ratio of IL-10 to TNFα was higher in non-survivors (median 6·9 [3·0–21·0]) than in survivors (median 3·9 [2·0–7·0], p=0·040). This ratio was highest in patients who died without underlying disease (median 21·5 [5·0–25·0]). Age, sex, and duration of fever before admission did not explain the differences in IL-10 and TNFα.

Interpretation

An anti-inflammatory cytokine profile of a high ratio of IL-10 to TNFα is associated with fatal outcome in febrile patients with community-acquired infection. Our findings caution against a widespread use of proinflammatory cytokine inhibition in patients with sepsis.

Introduction

We have suggested that an innate anti-inflammatory cytokine profile contributes to fatal meningococcal disease,1, 2 based on first-degree relatives of patients with fatal meningococcal disease having high ratios of the anti-inflammatory cytokine interleukin 10 (IL-10) to the proinflammatory cytokine tumour necrosis factor α (TNFα) after whole-blood stimulation in vitro. Studies in families, monozygotic twins, healthy individuals, and patients with sepsis have shown that the production of proinflammatory and anti-inflammatory cytokines is largely influenced by genetic factors.2, 3, 4 This finding raises the possibility that an innate cytokine profile after inflammatory insults substantially influences the outcome in infectious diseasēs.

Genetically-determined resistance and susceptibility of the host to infection with specific pathogens has received much attention and has been studied extensively in animal models.5, 6, 7 However, little is known about host factors in human beings, which on infection, direct the cytokine cascade in a proinflammatory or anti-inflammatory direction, and whether such factors substantially influence the outcome of disease.8 We investigated whether an anti-inflammatory cytokine profile is associated with an adverse outcome of infectious diseases. We measured plasma concentrations of IL-10 and TNFα in patients who presented to hospital with fever, in early and advanced stages of systemic inflammatory reaction.

Section snippets

Patients and methods

We did this study at the Leiden University Hospital, an 800-bed secondary and tertiary referral centre. We included over an 18-month period 464 patients aged older than 18 years consecutively admitted to the accident and emergency department because of community-acquired febrile illness (rectal temperature ≥38·2°C). Another 16 patients were enrolled but were excluded because they did not meet the inclusion criteria, adequate data could not be collected, or because they were lost to follow-up.

We

Results

We included 272 men and 192 women. The median age was 61 years (range 18–97). About 70% of the patients were referred to the hospital by their family physician, 18% by another physician, and the rest were self-referred. 61 (13·1%) patients had received oral antibiotic treatment in the week before admission, whereas 65 (14·0%) had received some kind of therapy that may have been immunosuppressive, such as low-dose oral prednisone for chronic obstructive pulmonary disease.

On admission, 332

Discussion

The anti-inflammatory cytokine profile associated with mortality that we identified is characterised by a high ratio of IL-10 to TNFα. These data extend to community-acquired infections our previous findings that an anti-inflammatory cytokine profile is an innate host characteristic that contributes to fatal meningococcal disease.1, 2

In at least 85% of the cases in this study, the fever on hospital admission was definitely caused by an infection in the respiratory or urinary tract. The patients

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